Interrelation between the analgesic and ulcerogenic action of cysteamine

Interrelationship was studied between the influence of cysteamine on pain threshold and ulcerogenic effect on the duodenum. Cysteamine (350 mg/kg) induced analgesia in mice which was prevented by naloxone (1.5 mg/kg). In rats, cysteamine produced duodenal ulcers with concomitant analgesia. The intensity of ulceration was higher in animals with lower basal pain threshold. The correlation between central and peripheral effects of endogenous opioids in the development of experimental duodenal ulcers is discussed.     

Computer search for molecular mechanisms of ulcerogenic action of non-steroidal anti-inflammatory drugs

Peptic ulcers are the most frequent side effect of therapy with non-steroidal anti-inflammatory drugs (NSAIDs). Good experimental evidence exists that pathogenesis of peptic ulcers cannot be attributed only to inhibition of cyclooxygenases. The knowledge about other molecular mechanisms of drug action associated with development of peptic ulcers could be useful for design of new safer NSAIDs. However, considerable time and material resources are needed for corresponding experimental studies. For simplification of the experimental search, we have developed an approach for in silico identification of putative molecular mechanisms of drug actions associated with their side effects. We have generated a data set of 85 NSAIDs, which includes information about their structures and side effects. Unknown molecular mechanisms of action of these NSAIDs were evaluated by the computer program PASS (Prediction of Activity Spectra for Substances) predicting more than 3000 molecular mechanisms of action based on structural formula of sub-stances. Statistically significant associations have been found between predicted molecular mechanisms of action and development of peptic ulcers. Twenty six molecular mechanisms of action probably associated with development of peptic ulcers have been found: two of them were known previously and 24 were quite new. Analyzing Gene Ontology data, data on signal and metabolic pathways, and available MEDLINE publication data, we proposed hypotheses on the role of 10 molecular mechanisms of action in the pathogenesis of peptic ulcer.     

Comparative study of hepatoprotective action of remaxol, reamberin and ademethionine in liver injury induced by antituberculosis drugs (experimental study)

The hepatoprotective activity of remaxol, reamberin and ademethionine was studied on a model of the liver injury induced by antituberculosis drugs. The study included 30 male uninbred albino rats. The following antituberculosis drugs were used: isoniazid (50 mg/kg) subcutaneously + rifampicin (250 mg/kg) intragastrically + pyrazinamide (45 mg/kg) intragastically (by the procedure of Yu. I. Slivka, 1989). Remaxol, reamberin and ademethionine were administered 1.5 hour prior to the antituberculosis drugs. The treatment course was 14 days. It was shown that remaxol, reamberin and ademethionin were able to correct the structural and functional disorders in the liver due to the use of the antituberculosis drugs. By the impact on the biochemical indices, evident of the liver function condition, remaxol showed the maximum effect. The effect of ream-berin was somewhat lower and the results of the ademethionine use were less significant. Remaxol had also a distinct effect as for lowering the level of the structural injuries in the liver, evident from recovery of the organ histoarchitectonics, less extended carbohydrate, albuminous and fatty degeneration, more active intracellular regeneration. It was noted that ademethionine had an insignificant effect on necrobiosis. Moreover, there was once detected a large necrosis focus, evident of possible stimulation of the liver tissue alteration by the drug.     

Local action of the chromatin assembly factor CAF-1 at sites of nucleotide excision repair in vivo

DNA damage and its repair can cause both local and global rearrangements of chromatin structure. In each case, the epigenetic information contained within this structure must be maintained. Using the recently developed method for the localized UV irradiation of cells, we analysed responses that occur locally to damage sites and global events triggered by local damage recognition. We thus demonstrate that, within a single cell, the recruitment of chromatin assembly factor 1 (CAF-1) to UV-induced DNA damage is a strictly local phenomenon, restricted to damage sites. Concomitantly, proliferating cell nuclear antigen (PCNA) locates to the same sites. This localized recruitment suggests that CAF-1 participates directly in chromatin structural rearrangements that occur in the vicinity of the damage. Use of nucleotide excision repair (NER)-deficient cells shows that the NER pathway--specifically dual incision--is required for recruitment of CAF-1 and PCNA. This in vivo demonstration of the local role of CAF-1, depending directly on NER, supports the hypothesis that CAF-1 ensures the maintenance of epigenetic information by acting locally at repair sites.     

Roles of endogenous prostaglandins and nitric oxide in gastroduodenal ulcerogenic responses induced in rats by hypothermic stress.

We examined the roles of endogenous prostaglandins (PGs) and nitric oxide (NO) in the gastroduodenal ulcerogenic responses to hypothermic stress (28 approximately 30 degrees C) in anesthetized rats. Lowering body temperature provoked damage in the gastroduodenal mucosa, with an increase of gastric acid secretion and motility. These responses were completely abolished by bilateral vagotomy or atropine, while 16,16-dimethyl PGE2 decreased the mucosal ulcerogenic response with no effect on acid secretion. The non-selective COX inhibitors, indomethacin or aspirin, worsened these lesions with enhancement of gastric motility and no effect on acid secretion, while the selective COX-2 inhibitor NS-398 did not affect any of these responses. On the other hand, the non-selective NOS inhibitor L-NAME but not aminoguanidine (a relatively selective inhibitor of iNOS), significantly potentiated the acid secretory and mucosal ulcerogenic responses in the stomach but reduced the duodenal damage in response to hypothermia, the effects being antagonized by co-administration of L-arginine. Hypothermia itself decreased duodenal HCO3- secretion under both basal and mucosal acidification-stimulated conditions. Both indomethacin and aspirin further decreased the HCO3- response to the mucosal acidification, while L-NAME significantly increased the HCO3- secretion even under hypothermic conditions, similar to 16,16-dimethyl PGE2. These results suggest that 1) hypothermic stress caused an increase of acid secretion and motility as well as a decrease of duodenal HCO3-secretion, resulting in damage in both the stomach and duodenum, 2) the COX-1 but not COX-2 inhibition worsened these lesions by enhancing gastric motility and further decreasing duodenal HCO3- response, 3) the cNOS but not iNOS inhibition worsened gastric lesions by increasing acid secretion but decreased duodenal damage by increasing HCO3- secretion. Thus, it is assumed that the gastroduodenal ulcerogenic and functional responses to hypothermic stress are modified by cNOS/NO as well as COX-1/PGs.     

Indices of acute inflammation against a background of lithium oxybutyrate action

The experiments on rats have shown that intraperitoneal administration of silver nitrate solution induces peritonitis while subplantar histamine, serotonin and prostaglandin E2 administration leads to an acute paw edema. Preliminary subcutaneous injection of lithium hydroxybutyrate prevents the development of inflammation.     

Mechanism of the action of the delta sleep-inducing peptide against a background of L-DOPA administration

A reciprocal nature of the shifts in activity of type A and B monoamine oxidases has been observed under the effect of DSIP against the background of L-DOPA administration (50 micrograms/kg) in the subfractions from the rabbit sensorimotor cortex. The results suggest that the activation of type A monoamine oxidase and serotoninergic system is the basis of the adaptive behavior of animals.     

Gastric mucosal susceptibility for ulcerogenic effect of indometacin at different time points of streptozotocin-induced diabetes development

In the study, we examined the gastric mucosal susceptibility for ulcerogenic effect of indometacin at different time points of streptozotocin-induced diabetes development. Indometacin was injected at ulcerogenic dose (35 mg/kg, s. c.) on days 3, 7 and 30 after streptozotocin administration (60 mg/kg, i. v.) or its vehicle to fasted rats. Typical diabetic hyperglicaemia was observed as early as in 3 days after streptozotocin administration and accompanied with enhanced mucosal susceptibility for indometacin as compared with that of control group. In 7 and 30 days after streptozotocin administration, when hyperglicaemia was still present, the average areas of indometacin-induced erosion increased 2- and 3-fold, respectively, as compared with those observed in 3 day after streptozotocin administration. The data obtained demonstrate that gastric mucosal susceptibility for the ulcerogenic effect of indometacin is increased at the early stages of diabetes development and then aggravates along with further development of the pathological condition.     

Tag team action at the synapse

Communication between neurons relies on chemical synapses and the release of neurotransmitters into the synaptic cleft. Neurotransmitter release is an exquisitely regulated membrane fusion event that requires the linking of an electrical nerve stimulus to Ca(2+) influx, which leads to the fusion of neurotransmitter-filled vesicles with the cell membrane. The timing of neurotransmitter release is controlled through the regulation of the soluble N-ethylmaleimide sensitive factor attachment receptor (SNARE) proteins-the core of the membrane fusion machinery. Assembly of the fusion-competent SNARE complex is regulated by several neuronal proteins, including complexin and the Ca(2+)-sensor synaptotagmin. Both complexin and synaptotagmin bind directly to SNAREs, but their mechanism of action has so far remained unclear. Recent studies revealed that synaptotagmin-Ca(2+) and complexin collaborate to regulate membrane fusion. These compelling new results provide a molecular mechanistic insight into the functions of both proteins: complexin 'clamps' the SNARE complex in a pre-fusion intermediate, which is then released by the action of Ca(2+)-bound synaptotagmin to trigger rapid fusion.     

Dynamic action of neurometals at the synapse

There are synaptic vesicles that are labeled by Timm's sulfide-silver staining method in the brain, suggesting that synaptic vesicles contain metals such as zinc and copper. Zinc is co-released with glutamate and the importance of zinc signaling in the intracellular compartment, in addition to extracellular compartment, is becoming recognized. Zinc can pass through calcium channels, while blocking them. Calcium signaling plays a critical role for synaptic activity and crosstalk between zinc signaling with calcium signaling through calcium channels may participate in synaptic neurotransmission including synaptic plasticity such as long-term potentiation. Copper released into the synaptic cleft during synaptic excitation may also participate in synaptic neurotransmission. Other metals including copper potentially serve as calcium channel blockers and also influence calcium signaling and zinc signaling via the interaction with metal-binding proteins such as metallothioneins. Homeostasis of metals needs to be controlled spatiotemporally for proper brain function, and their dyshomeostasis is associated with neurological diseases. However, the data on the dynamic action of metals at synapses is limited and their significance poorly understood. This paper summarizes the action of metals in synaptic neurotransmission focused on calcium signaling at glutamatergic synapses.     

Mechanical stress induces DNA synthesis in PDL fibroblasts by a mechanism unrelated to autocrine growth factor action

Periodontal regeneration is thought to require the proliferation of stress-sensitive periodontal ligament (PDL) fibroblast cells. The influence of physiological amounts of mechanical stretching on the DNA synthesis potential of human PDL fibroblasts was examined by means of an established, simple in vitro system of stretch application. A significant increase in the relative levels of incorporation of tritiated thymidine was observed in cultures stretched for 1–6 h. Neutralising antibodies for platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β) did not blunt the DNA synthesis induction. This mitogenic response to stretch appears to be independent of an autocrine mechanism involving growth factors in general, because stretch-conditioned medium, when transferred to non-stretched fibroblasts, did not mimic the mitogenic effect of stretch.     

Oxidative stress involved in the antibacterial action of different antibiotics

Staphylococcus aureus and Escherichia coli sensitive to chloramphenicol incubated with this antibiotic suffered oxidative stress with increase of anion superoxide (O2-). This reactive species of oxygen was detected by chemiluminescence with lucigenin. S. aureus, E. coli, and Enterococcus faecalis sensitive to ciprofloxacin exhibited oxidative stress when they were incubated with this antibiotic while resistant strains did not show stimuli of O2-. Other bacteria investigated was Pseudomonas aeruginosa, strains sensitive to ceftazidime and piperacillin presented oxidative stress in presence of these antibiotics while resistant strains were not stressed. Higher antibiotic concentration was necessary to augment O2- in P. aeruginosa biofilm than in suspension, moreover old biofilms were resistant to oxidative stress caused by antibiotics. A ceftazidime-sensitive mutant of P. aeruginosa, coming from a resistant strain, exhibited higher production of O2- than wild type in presence of this antibiotic. There was relation between antibiotic susceptibility and production of oxidative stress.